Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

The optimal timing of hepatitis C therapy in liver transplant-eligible patients: Cost-effectiveness analysis of new opportunities.

Different strategies of DAAs treatment are currently possible both pre- and postliver transplantation (LT). Clinical and economic consequences of these strategies still need to be adequately investigated; this study aims at assessing their cost-effectiveness. A decision analytical model was created to simulate the progression of HCV-infected patients listed for decompensated cirrhosis (DCC) or for hepatocellular carcinoma (HCC). Three DAAs treatment strategies were compared: (i) a 12-week course of DAAs prior to transplantation (PRE-LT), (ii) a 4-week course of DAAs starting at the time of transplantation (PERI-LT) and (iii) a 12-week course of DAAs administered at disease recurrence (POST-LT). The population was substratified according to HCC presence and, in those without HCC, according to the MELD score at listing. Data on DAAs effectiveness were estimated using a cohort of patients still followed by 11 transplant centres of the European Liver and Intestine Transplant Association and by data available in the literature. In this study, PRE-LT treatment strategy was dominant for DCC patients with MELD<16 and cost-effective for those with MELD16-20, while POST-LT strategy emerged as cost-effective for DCC patients with MELD>20 and for those with HCC. Sensitivity analyses confirmed PRE-LT as the cost-effective strategy for patients with MELD≤20. In conclusion, PRE-LT treatment is cost-effective for patients with MELD≤20 without HCC, while treatments after LT are cost-effective in cirrhotic patients with MELD>20 and in those with HCC. It is worth reminding, though, that the final choice of a specific regimen at the patient level will have to be personalized based on clinical, social and transplant-related factors.

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. -13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

[Evaluation of noninvasive diagnostic criteria for hepatocellular carcinoma on pretransplant MRI (2010): correlation between MR imaging features and histological features on liver specimen]. / Évaluation des critères diagnostiques non invasifs du carcinome hépatocellulaire sur IRM pré-greffe hépatique (2010) : corrélations IRM - anatomopathologiques sur explants hépatiques.

PURPOSE: To validate the 2010 diagnostic criteria from the American Association for the Study of Liver Diseases (AASLD) for hepatocellular carcinoma (HCC) on MRI using the surgical liver specimen as a gold standard. PATIENTS AND METHODS: A total of 21 liver transplant recipients were retrospectively included. Each underwent surgery because of HCC between January 2007 and January 2008. Pre-transplant MRI was performed on a 1.5 Tesla MR unit. The T1W and T2W signal and kinetic contrast enhancement were correlated for each lesion with the surgical specimen. Lesion diameters between MRI and specimen were compared (Spearman). A multivariate model was created (R statistics software package) to predict the presence and grade of tumor differentiation (WHO, Edmonson Steiner). RESULTS: A total of 71 nodules were detected at histology, including 54 HCC (mean size: 25.3mm) compared to 68 on MRI. There was moderate agreement (r=0.58, P<0.001) between the maximum lesion diameters measured on MRI and at histology. Wash-out on MRI provided an accuracy of 75 % for the detection of HCC (sensitivity=75 %, specificity=76 %). Adding T2W hyperintensity to the AASLD criteria increased the sensitivity of MRI from 70.3 % to 77.7 % for the diagnosis of HCC and from 67.6 % to 79 % for nodules less than 20mm in diameter, without affecting specificity. On multivariate analysis, wash out as a single variable was significantly associated with a diagnosis of HCC (P<0.01, odds ratio 12.0, CI 95 % [2.6-55.5]). T1W hyperintensity (P=0.04, odds ratio 5.4) and loss of signal on opposed-phase images (P=0.02, odds ratio 9.2) were predictive of good differentiation. CONCLUSION: On MRI, the AASLD criteria or presence of wash out within a liver nodule in patients with underlying chronic hepatocellular disease are suggestive of tumoral transformation. The addition of T2W hyperintensity to the AASLD criteria increases the detection of HCC, especially nodules smaller than 20mm.

Regression of new-onset diabetes mellitus after conversion from tacrolimus to cyclosporine in liver transplant patients: results of a pilot study.

INTRODUCTION: New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation. AIM: To evaluate the impact of conversion from tacrolimus to cyclosporine in liver transplant patients presenting NODM. METHOD: In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study. RESULTS: At month 12, NODM had significantly resolved (FBG<7 mmol/L without treatment) in 36% of patients (95% CI 20.8-51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L (P=0.008) and mean HbA(1c) decreased from 6.4 to 6.0% (P=0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L (P<0.001). CONCLUSIONS: These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required.

Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study.

We conducted a multicenter randomized study in liver transplantation to compare standard-dose tacrolimus to reduced-dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post-transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety-five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37-0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49-0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29-0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced-dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full-dose tacrolimus in adult liver transplantation.

[Liver transplantation for hepatocellular carcinoma and potential application of PSI]. / Carcinome hépatocellulaire et transplantation hépatique : rôle futur des inhibiteurs de la mTOR.

Liver transplantation is considered the best treatment of hepatocellular carcinoma but its efficacy depends on the risk of tumour recurrence. The risk of recurrence depends on tumour characteristics but is also influenced by immunosuppressive regimens. Immunosuppressants of the mTOR inhibitors family share anti-tumour properties which are already taken into account in the treatment of renal carcinoma and advanced hepatocellular carcinoma. These features make interesting their use in liver transplantation for hepatocellular carcinoma, with the following goals: to reduce the risk of post-transplant tumour recurrence, to expand the indications of liver transplantation for hepatocellular carcinoma and eventually to slow down tumour growth during the waiting period. However, to date, the potential role of mTOR inhibitors after liver transplantation for hepatocellular carcinoma is only based on small encouraging proof of concept studies. Large randomized studies are therefore required to further define the specific indications of these compounds. The demonstration of a beneficial impact of mTOR inhibitors in the setting of liver transplantation for hepatocellular carcinoma would be a major therapeutical advance.

[Hepatic transplantation]. / La transplantation hépatique.

The first liver transplantation (LT) was conducted in 1963. After a two-decade development phase with the improvement of surgical and anesthesia-resuscitation techniques, and a better control of allograft rejection, LT has become the benchmark treatment for the majority of end-stage liver diseases. Since the 1980s, indications of LT have gradually expanded and the current main indications in adults are hepatocellular carcinoma at an early stage (15 to 30% of indications), C cirrhosis (15 to 40% of indications) and alcoholic cirrhosis (20 to 25% of indications). Five thousand LTs are performed yearly in Europe, including 1000 LTs in France, with, over the 2000-2006 period, survival rates of 86, 75 and 68% at one, five and 10 years, respectively. Several advances have accompanied the increasing number of indications and these excellent results: (a) the development of more specific immunosuppressive drugs to prevent rejection, the incidence of which is currently less than 20%: tacrolimus, mycophenolic acid, anti-IL2 receptor antibodies, mTOR inhibitors, (b) a policy of active recruitment of organs together with surgical innovations (split liver, domino LT, living donor transplantation) contributing to the expansion of the pool of organs, (c) standardization of organ allocation policies, based on the sickest first policy. The applicability of LT, however, remains limited by the shortage of organs and the occurrence of long-term complications of immunosuppression. Due to the lack of effective alternative perspectives to LT for the treatment of end-stage liver diseases, the two major challenges for the liver transplant community should be the optimization of organ recruitment and the development of innovative immunosuppressive regimens able to overcome the side effects of current immunosuppressive drugs. The development of non heart beating donation and appropriate use of intrafamilial donation could partly compensate for the organ shortage in the midterm. The identification of molecular signatures in tolerant patients in whom immunosuppression could be stopped, and induction of tolerance, trough lymphocyte depletion or T lymphocyte costimulation blockade, are the most advanced research ways to reduce complications of immunosuppression.

Natural history and therapeutic management of recurrent hepatocellular carcinoma after liver transplantation.

While the natural history and appropriate diagnostic and management practices are relatively well defined for hepatocellular carcinoma (HCC), data are scarce concerning the characteristic features and treatment modalities for recurrent HCC after liver transplantation. The time of recurrence appears to impact survival more significantly than localization, but to date, guidelines for therapeutic management of recurrent HCC have not been established. Data in the literature shows that late and unifocal recurrence has a better prognosis when treated by surgery or radiofrequency. In the event of early recurrence, surgery cannot be recommended due to the lack of evidence and the high risk of advanced disease. Systemic therapy can be discussed in a situation of multifocal recurrence. Proliferative signal inhibitors exhibit both immunosuppressive and antiproliferative properties and liver transplantation teams tend to introduce such treatment despite the lack of extensive data.

Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2).

BACKGROUND: A prospective, open-label, study was conducted at 29 centers in 9 countries, involving 307 de novo liver transplant patients to compare the clinical usefulness of monitoring 2-hr post-dose cyclosporine (CsA) levels (C2) with conventional trough cyclosporine blood levels (pre-dose) (C0). METHODS: Neoral oral therapy was initiated at 15 mg/kg/day and dose adjusted according to predetermined C2 or C0 target level ranges. The primary efficacy variable was treatment failure at 3 months, where evaluation was based on a composite endpoint of biopsy-proven rejection, treatment for rejection, graft loss, death, or premature withdrawal/discontinuation from the study. RESULTS: Baseline characteristics were similar between groups. Graft loss at 12 weeks (retransplantation or death) occurred in 6.8% C2 and in 7.0% C0 patients. Overall incidence of treated acute rejection was lower for C2 (23.6%) than C0 patients (31.6%) (P=0.144, Cochran-Mantel-Haenszel [CMH] test). In hepatitis C virus (HCV)-negative patients, the incidence of rejection in the C2 group was significantly less than in the C0 group (21.2% vs. 33.0%; P<0.05), whereas in HCV-positive patients, the rejection rate was similar in both groups (26.7% for C2 group vs. 27.3% for C0 group: P=0.81). C2 patients (n=16) who reached minimum target CsA levels by day 3 had a notably low incidence of rejection (12.5%), whereas there was no difference in the incidence of rejection in C0 patients, irrespective of time to reach target level. For biopsy-proven acute rejections (21.6% for C2 vs. 30.4% for C0), the incidence of moderate and severe histological diagnosis was significantly lower in the C2 group than in the C0 group (47% vs. 73%; P=0.01). Safety profiles were similar between the two groups, with few patient withdrawals due to adverse events (9.5% for C2; 7.0% for C0). CONCLUSIONS: Using C2 monitoring, the overall incidence of acute cellular rejection was lower compared with the C0 group, and the histological severity of acute rejections was shown to be significantly milder for the C2 group, indicative of good long-term prognosis. These data demonstrate that the use of C2 monitoring is superior to C0 and results in a reduction in the incidence and severity of acute cellular rejection without detrimental effect on the drug safety profile.

[Liver transplantation: which indications? which results?]. / Transplantation hépatique: quelles indications? Quels résultats?

UNLABELLED: THE ONLY TREATMENT: Liver transplantation (LT) is currently the final treatment for most types of end-stage liver diseases including alcoholic cirrhosis, so far alcoholic cirrhosis has become the first indication for LT in France and other western countries, accounting for 25% of all procedures. However due to ethical issues and also the discrepancy between the theoretical number of candidates and available organs, indications for LT in alcoholic cirrhosis must be rigorously defined. INDICATIONS: On the average, candidates are 50 years old, males in two-thirds of the cases, with pre-terminal liver disease combining advanced-stage liver dysfunction (PT < 40%, bilirubin > 50 mumol/l, albumin < 30 g/l) and intractable ascitis. The gain in survival being best in patients with severe cirrhosis (Child-Pugh grade C), these patients should be given priority when liver function fails to improve despite prolonged abstention. For less advanced diseases (Child-Pugh B or A), LT can be considered after failure of symptomatic medical treatments or in case a small hepatocellular carcinoma develops. CONTRAINDICATIONS: The list includes presence of extrahepatic organ failure, generally related to alcohol-tobacco abuse (cardiomyopathy, pancreatitis, neuropathy, squamous cell carcinoma ...) and precarious psychosocial situations exposing the patient to the risk of recurrent alcoholism and non-compliance after transplantation. Predictive factors of after recidivism after transplantation are preoperative abstinence of less than 6 months duration, denial of alcoholism, lack of familial and occupational support, antisocial behavior and a history of psychiatric disorders or drug abuse. Patients with several of these risk factors cannot reasonably be considered as candidates for LT. Inversely, transplantation should be proposed for patients with no or few risk factors due to the excellent physical and social outcome observed. Generally, a full 6 months of preoperative abstinence is required by most transplantation centers. The aim is to avoid underestimation for liver function recovery and to limit the risk of recurrent alcoholism. RESULTS: Using the above criteria, LT for alcoholic cirrhosis can restore a satisfactory quality of life and provides a 5-year survival to the order of 65%, similar to results obtained in other indications for LT. Recurrent pathological consumption of alcohol occurs in 10 to 15% of the cases, generally with moderate effects on the liver graft. PRACTICAL ATTITUDE: Using the currently accepted selection criteria, less than 5% of the patient with alcoholic cirrhosis actually undergo transplantation. For these patients, LT enables to treat both cirrhosis and alcoholic disease in 80% of the cases. Based on these results, segregating among patients with severe alcoholic cirrhosis considered as reasonable candidates for LT after a complete pluridisciplinary preoperative work-up must be avoided.

Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial.

Severe T-cell immunodeficiency after solid organ or bone marrow transplantation may result in the uncontrolled outgrowth of latently Epstein-Barr virus-infected B cells, leading to B-lymphoproliferative disorder (BLPD). Given the potentially important pathogenic role of IL-6 in BLPD, it was tested whether the in vivo neutralization of IL-6 by a monoclonal anti-IL-6 antibody could contribute to the control of BLPD. Safety and efficacy were assessed in 12 recipients of transplanted organs who had BLPD refractory to the reduction of immunosuppression over 8 days. Five patients received 0.4 mg/kg per day. The next 7 patients received 0.8 mg/kg per day. Treatment was scheduled to last 15 days. It was completed in 10 patients, and in the other 2 patients was discontinued early (days 10 and 13, respectively) because of disease progression. Treatment tolerance was good, and no major side effects were observed. High C-reactive protein levels were found in 9 patients before treatment but were normalized under treatment in all patients, demonstrating efficient IL-6 neutralization. Complete remission (CR) was observed in 5 patients and partial remission (PR) in 3 patients. Relapse was observed in 1 of these 8 patients in whom remission was observed. This relapse was unresponsive to treatment. Disease was stable in 1 patient, but it progressed in 3 patients. Seven patients are alive and well. Two patients died because of disease progression, and 3 patients died while in CR (chronic rejection in 2 patients and BLPD sequelae in 1 patient). These data suggest that the anti-IL-6 antibody is safe and should be further explored in the treatment of BLPD.